The hormone oxyntomodulin (OXM, glucagon-37) is a posttranslational product of preproglucagon processing in the intestine and central nervous system (CNS) and is secreted from L-cells in the gut in response to food intake. Discovered in 1983, OXM has been implicated in the regulation of food intake and energy expenditure. Central or peripheral administration of OXM in rats causes a decrease in short term food intake with minimal effects on gastric emptying (Dakin et al. Endocrinology, 142:4244-4250 (2001), Dakin et al. Endocrinology, 145:2687-2695 (2004)). Repeated intracerebroventricular administration of OXM in rats results in elevated core temperatures and reduced weight gain compared to pair-fed animals, suggesting effects on both caloric intake and energy expenditure (Dakin et al. Am. J. Physiol. Endocrinol. Metab., 283:E1173-E1177 (2002)).
OXM is a 37-amino acid peptide. It has been reported that the effects of OXM in inhibiting gastric acid secretion can be mimicked by the 8-residue C-terminal fragment Oxm(30-37), known as SP-1 (Caries-Bonnet et al., Peptides, 1996, 17:557-561. In humans, a single 90 min intravenous infusion of OXM in normal weight healthy subjects reduced hunger scores and food intake at a buffet meal by ˜19%. Cumulative 12 hour caloric intake was reduced by ˜11% with no reports of nausea or changes in food palatability (Cohen et al., J. Clin. Endocrinol. Metab., 88:4696-4701 (2003)). More recently, pre-prandial injections of OXM over a 4 week period in obese healthy volunteers (BMI ˜33) led to a significant reduction of caloric intake on the first day of treatment (˜25%) that was maintained over the course of the study (35% reduction after 4 weeks) (Wynne et al., Diabetes 54:2390-2395 (2005)). Robust weight loss was observed at the end of the study in treated subjects (1.9%, placebo-corrected). Plasma levels of OXM were similar to that observed in the infusion study (peak concentration ˜950 pM). The absence of any tachyphylaxis and a low incidence of mild and transient nausea (˜3%) despite the relatively high doses necessitated by the poor in vivo stability of OXM (plasma t1/2<12 min) renders this hormone one of the few obesity targets with both human validation and an attractive tolerability profile.
OXM has a very short half-life and is rapidly inactivated by the cell surface dipeptidyl peptidase IV (hereafter DP-IV). However, DP-IV inhibitors are weight-neutral in the clinic, suggesting that supraphysiological levels of OXM (900-1000 pM) may be required to achieve weight loss in humans.
Oxyntomodulin therefore shows potential as a treatment for metabolic disorders such as diabetes and obesity. However, because of the poor in vivo stability of OXM, there exists a need to develop OXM derivatives that can be safely and efficaciously administered for the treatment of metabolic diseases, such as diabetes and obesity. It would be further desirable if analogs or derivatives were developed that were modified by conjugation to moieties that would improve stability and pharmacokinetics, more particularly modifications that confer resistance to DP-IV cleavage. The instant invention provides OXM polypeptide derivatives and methods for the treatment or prevention of metabolic disorders such as obesity and diabetes by administering the derivatives described herein.